Controversal question: Can the target doses of medications such as those defined in morbidity-mortality trials in heart failure patients be realistically achieved in clinical routine?



Can the target doses of medications such as those defined in morbidity-mortality trials in heart failure patients be realistically achieved in clinical routine?
1. E. Amosova, J. Rudenko, A. Bezrodnyi, Ukraine
2. E. A. Bocchi, Brazil
3. M. Degertekin, Turkey
4. S. V. Konstantinides, Greece
5. H. Krum, Australia
6. L. P. Low, Singapore
7. V. Mareev, Russia
8. K. McDonald, Ireland
9. J. Rajadurai, Malaysia
10. K. Sliwa, South Africa
11. B. D. Westenbrink, W. H. van Gilst, The Netherlands




1. E. Amosova, J. Rudenko, A. Bezrodnyi, Ukraine


Kateryna AMOSOVA, MD, PhD
Professor and Chief of Internal Medicine
Department No. 2
National Medical University named
after O. O. Bogomolet
13, Shevchenko Boulevard
Kyiv 01004, UKRAINE

(e-mail: nancy@gala.net)



Numerous observational studies have demonstrated that “real life” heart failure (HF) patients receive lower medication doses than the targets recommended in guidelines. The problem is more widespread for β-blockers than for angiotensin-converting enzyme inhibitors because of their many contraindications and side effects. Even in outpatients treated by cardiologists, only 18% to 21% actually receive target doses of β-blockers.1

The low incidence of optimal uptitration is partly due to differences between patient populations in real life and randomized trials. Real-life patients are much older, with higher incidences of severe HF with low blood pressure and concomitant somatic diseases, general fragility, and psychiatric diseases/ dementia. The main independent predictor of β-blocker undertitration is age.2 Observational studies report that low heart rate (HR) at rest is not a limiting factor in achieving target dose, however. Another reason for undertitration is overestimation of the risk of side effects. In a comparatively small (n=169) prospective randomized trial,3 the use of supervised nurse facilitators when initiating and titrating β-blockers resulted in 43% reaching target doses, compared with 10% in usual practice. Thus, achievement of guideline-recommended target doses in clinical practice, at least for β-blockers, appears unrealistic.

At least two questions arise: to what extent is the clinical effect of β-blockers dose dependent in HF? How sound is the use of empirically chosen target doses? There are few large, multicenter, prospective randomized dose-ranging β-blocker trials with clinical end points. In the small (n=345) randomized Multicenter Oral Carvedilol Heart failure Assessment (MOCHA), treatment with carvedilol was associated with a small dose-related improvement of ejection fraction and survival. Both parameters, however, were not prespecified end points. Importantly, HR reduction at all three doses was dose related, though minimally.

In a retrospective subgroup analysis in Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERITHF), compared with placebo, relative reduction inmortality was the same in patients uptitrated to metoprolol ≤100 mg and >100 mg daily, and associated with identical on-treatment and basal HR.

Similar results were obtained in a retrospective subgroup analysis of patients enrolled in Cardiac Insufficiency Bisoprolol Study II (CIBIS II). No significant differences were found in baseline, final, and absolute HR reduction with three doses of bisoprolol.4

A meta-analysis demonstrated that the survival benefit of β- blockers in HF patients is associated with magnitude of HR reduction but not drug dose.5 For every 5 beats per minute (bpm) HR reduction, there was an 18% reduction in risk of death.

The notion of HR as a risk factor and intervention target in HF was confirmed in Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT).6 HR reduction with the selective If channel blocker ivabradine in patients with sinus rhythm ≥70 bpm was associated with an 18% reduction in cardiovascular death and hospitalization for HF (primary end point), although without influencing cardiovascular and allcause mortality. All patients received optimal treatment, including maximal tolerated β-blocker doses. The comparative clinical effect of pure HR reduction versus inhibition of all sympathetic stimulation by β-blockade in HF patients can only be obtained through specially planned prospective randomized trials directly comparing the two strategies.

In the meantime, it seems reasonable to consider that the target dose of β-blocker in HF is not a fixed dose, but the maximal tolerated dose or dose needed to lower sinus rhythm to 60-70 bpm at rest. The latter is probably a pathophysiologically sound target. If this target isn’t reached at the maximal tolerated β-blocker dose, which is what happens in the majority of real life patients, the evidence-based treatment strategy should be the addition of ivabradine. _

References
1. De Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey. Eur J Heart Fail. 2007;9:1205-1211.
2. Dahlstrom1 U, Hakansson J, Swedberg K, Waldenstrom A. Adequacy of diagnosis and treatment of chronic heart failure in primary health care in Sweden. Eur J Heart Fail. 2009;11:92-98.
3. Ansari M, Shlipak MG, Heidenreich PA, et al. Improving guideline adherence. A randomized trial evaluating strategies to increase -blocker use in heart failure. Circulation. 2003;107:2799-2804.
4. Simon T, Mary-Krause M, Funck-Brentano C, Lechat PH, Jaillon P; CIBIS II Investigators. Bisoprolol dose–response relationship in patients with congestive heart failure: a subgroup analysis in the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Eur Heart J. 2003;24:552-559.
5. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: β-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794.
6. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. 2010;12(1):75-81.




2. E. A. Bocchi, Brazil


Edimar Alcides BOCCHI, MD
Heart Institute of the São Paulo
University Medical School
Rua Dr Melo Alves 690, 4o andar
São Paulo, CEP 01417-010
BRAZIL

(e-mail: dcledimar@incor.usp.br)


Every day, clinicians face difficult decisions on how best to manage heart failure (HF) patients. Ideally, these decisions are guided by the best medical evidence. Clinical practice guidelines are designed to translate medical research and expert opinion into recommendations for everyday practice, but in the case of HF, doctors are reticent or slow to incorporate these recommendations.1 Clinical practice guidelines are ultimately a consensus developed to help patients, but what many people say collectively, no one believes individually.2

Among the obstacles to guideline implementation are the general resistance to changing patterns of practice, loss of professional autonomy, concern about litigation, potential economic disincentives, inadequate skill sets, lack of technological support, the “does not apply to my patient” mindset, and an out of date/moving target.2 Another limiting factor is patient preference in treatment decisions, which is a challenge for doctors.

With regard to HF, although physicians are increasingly encouraged to apply guidelines in their practice, it has repeatedly been observed that a considerable proportion of patients do not receive evidence-based treatment. Additional factors to explain this could be lack of knowledge, expertise, and time, and the concept that trials enroll highly selected patients.

One additional challenge in the implementation of guidelines in clinical practice is use of the recommended dose, or the doses that showed benefit in trial patients. One study found that patients who would be eligible for trials were being treated with at least half the target dose, and 40%-50% were receiving the minimum dose recommended by regulatory authorities.3 With regard to β-blockers, 54% of patients eligible for Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) received a β-blocker, of whom 20% received at least half the target dose, and only 6% received the full target dose. In a subgroup of the aforementioned trial-eligible patients, barely half were prescribed a β-blocker, with doses lower than those proven to be effective in large controlled trials. Lack of similarity between HF patients in clinical practice and clinical trials thus does not adequately explain underutilization of therapy.

Obstacles to use of target doses of β-blockers include the need for close care, progressive uptitration in treatment of HF, repeated assessments to monitor individual responses, and an effective HF follow-up program. Symptoms of HF such as hypotension, dyspnea, and weakness during exercise can be confused with side effects of β-blockers. Treatment with β-blockers can provoke an initial worsening of symptoms. Doctors can consider introduction or uptitration of β-blockers to be a cause of decompensated HF during hospitalization. Doctors may already be satisfied with the symptomatic improvement with smaller doses of drugs, and therefore not push for the higher targets in order to avoid adverse events. The result is that doctors in clinical practice do not prescribe— or patients are not using—optimal doses of β-blockers.

The question is whether to persist only in the implementation of guideline-recommended doses, or to accept the real world and look for additional therapies.

Logically, the initial impetus is only to develop strategies to improve adherence to guideline-recommended doses. Many publications have shown the limitations of this strategy, however, although this initiative should never be abandoned. In real life, nevertheless, alternative and additional treatments should be investigated to resolve this difficult issue. The recent publication concerning the effects of ivabradine on HF, which showed a reduction in hospital admissions for worsening HF and deaths due to HF, is a positive and important example.4

In summary, the prescription of target doses is very important in the treatment of HF. However, in the real world, the association of new effective drugs and treatment strategies should form an additional therapeutic approach. _

References
1. Ansari M, Shlipak MG, Heidenreich PA, et al. Improving guideline adherence: a randomized trial evaluating strategies to increase beta-blocker use in heart failure. Circulation. 2003;107:2799-2804.
2. Armstrong PW. Do guidelines influence practice? Heart. 2003;89:349-352.
3. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J. 2005;26:2706-2713.
4. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.




3. M. Degertekin, Turkey


Muzaffer DEGERTEKIN, MD, PhD, FESC
Professor of Cardiology
Department of Cardiology
Yeditepe University Hospital
Istanbul, TURKEY

(e-mail: mdegertekin@yeditepe.edu.tr)


Chronic heart failure (CHF) is a condition characterized by unpleasant symptoms, high mortality, and recurrent and lengthy hospitalizations. It is a major public health concern of growing prevalence. The short-term goals of CHF management are directed toward relieving symptoms and improving functional capacity and quality of life. Long-term goals include reducing mortality and slowing or reversing the underlying cardiac structural abnormalities associated with CHF. Two decades of controlled clinical trials have led to significant developments in the treatment of heart failure. The results of these large placebo-controlled randomized trials have been integrated into European and US treatment guidelines. These guidelines emphasize in particular the beneficial effects on mortality and morbidity of angiotensinconverting enzyme (ACE) inhibitors, β-blockers, angiotensin II receptor blockers (ARBs), and aldosterone antagonists. However, several national and international surveys consistently suggest there is suboptimal utilization of recommended medications in outpatients, as well as in hospital situations.1,2 One reason for this could be that CHF remains underdiagnosed and undertreated. Undertreatment may mean either underuse of modern recommended treatments, or prescription of low doses of these drugs.3

A survey performed to assess awareness of CHF management recommendations in Europe among cardiologists, internists, geriatricians, and primary care physicians showed that although each physician group lacked complete adherence to guideline-recommended management strategies, they were used significantly less well by internists, geriatricians, and primary care physicians, indicating the need for education of these essential health care providers.4 The Euro Heart Failure Survey, performed in 116 hospitals across 24 European Society of Cardiology countries, showed suboptimal utilization of ACE inhibitors and β-blockers—particularly the latter. The Impact-Reco study, which compared heart failure management strategies before and after publication of updated heart failure guidelines by the European Society of Cardiology, found a significant improvement post publication. Analysis of the reasons for nonprescription or for not reaching target doses suggested that advanced age (>75 years), contraindications, comorbidities such as renal failure, and side effects all played major roles.

Interestingly, use and dosage of evidenced-based drugs in the treatment of CHF is influenced by patient, but also physician, gender.5 The gap between guideline recommendations and clinical routine is an important issue; suboptimal treatment should be avoided by all physicians involved in the care of CHF patients. However, when considering whether everyday practice is suboptimal, an important question arises: is more always better, and should dosage recommendations be followed in all patients? Although it is recommended that doses be uptitrated to high target levels as defined in the original trial protocols, the superiority of high versus low-tomoderate doses of these drugs in reducing CHF mortality has not been documented convincingly. The reduction in totalmortality, sudden death, and death from worsening heart failure was in the same range in two major β-blocker trials Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT- HF) and Cardiac Insufficiency BIsoprolol Study II (CIBIS II).

Furthermore, the combination of ACE inhibitors and ARBs showed no clear clinical advantage, but increased the risk of adverse effects such as symptomatic hypotension, worsening renal function, and hyperkalemia. There are also well-known data documenting increased risks with higher doses of digoxin, diuretics, and spironolactone.6

In conclusion, guideline-recommended doses of drugs remain the scientifically validated basis for treatment in all patients with CHF. The additive therapeutic effects of β-blockers and ACE inhibitors can improve prognosis regardless of age and comorbid conditions. However, instead of dogmatic enforcement of high target doses, the dose should be adapted individually, taking into consideration particular characteristics of certain patient subpopulations. Low initial doses and slower uptitration will improve the acceptance of heart failure drugs, thus enabling a more accurate application of the guidelines. _

References
1. Komajda M, Follath F, Swedberg K, et al; Study Group of Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology. The EuroHeart Failure Survey programme: a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J. 2003;24:464-474.
2. Cleland JG, Cohen-Solal A, Aguilar JC, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet. 2002;360:1631-1639.
3. Taubert G, Bergmeier C, Andresen H, Senges J, Potratz J. Clinical profile and management of heart failure: rural community hospital vs. metropolitan heart center. Eur J Heart Fail. 2001;3:611-617.
4. Remme WJ, McMurray JJ, Hobbs FD, et al; SHAPE Study Group. Awareness and perception of heart failure among European cardiologists, internists, geriatricians, and primary care physicians. Eur Heart J. 2008;29:1739-1752.
5. Baumhäkel M, Müller U, Böhm M. Influence of gender of physicians and patients on guideline-recommended treatment of chronic heart failure in a crosssectional study. Eur J Heart Fail. 2009;11:299-303.
6. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006;27:178-186.




4. S. V. Konstantinides, Greece


Stavros V. KONSTANTINIDES,
MD, PhD, FESC
Professor and Chairman
Department of Cardiology
Democritus University of Thrace
University General Hospital
68100 Alexandroupolis
GREECE

(e-mail: skonst@med.duth.gr)


Beta-blockers form an essential part of the standard care of patients with systolic chronic heart failure, and current guidelines recommend uptitration to the target dose in order to maximize therapeutic benefit.1 This recommendation is based on high-quality clinical data supporting a dosedependent beneficial effect of these agents on patient prognosis.2-5 However, β-blocker target doses are often difficult to achieve in clinical routine; in fact, they have even proven difficult to achieve in the clinical trial setting. In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), the mean daily dose of study drug in the metoprolol group was 159 mg once daily, with (only) 64% of patients receiving the target dose of 200 mg once daily. Similar or lower target-dose rates were achieved in further landmark trials such as Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS), Cardiac Insufficiency BIsoprolol Study II (CIBIS II), and Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS).2-5 Of note, reasons for not reaching target doses, or even discontinuing β-blockers in heart failure patients, often remained obscure. For example, in SENIORS, the main reason for discontinuation of nebivolol was reportedly “patient’s decision” (10% patients).5 As expected, β-blocker target-dose rates are even lower in the “real world.” A national cohort study in the UK revealed that less than 40% of heart failure patients were treated with a β-blocker, and less than 20% treated with a guideline-recommended agent achieved target dose. As in clinical trials, the reasons for not being treated with a β-blocker or achieving target dose remained obscure for a large proportion (>50%) of patients.5

There are several possible reasons for β-blocker undertreatment, poor tolerance being most commonly reported. Besides bradycardia and hypotension, β-blockers may cause fatigue, depression, and erectile dysfunction. Patients experiencing β-blocker–related undesirable effects at the initiating dosage are very likely not to tolerate target doses. Persistence in the prescription of higher doses in such cases will result in discontinuation or poor adherence. Thus, what represents the optimally efficacious and safe β-blocker dose for an individual patient with heart failure may not necessarily be the dose dogmatically extrapolated from clinical trials.

An important part of the beneficial effect of β-blockade in heart failure is attributed to heart rate reduction. A clear relationship between change in heart rate with β-blockers and allcause mortality has been demonstrated in heart failure patients. This concept is supported by the recently published Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), assessing the effect on heart failure outcomes of heart rate reduction by the selective sinus-node inhibitor ivabradine.6 In SHIFT, 90% of study participants were treated with a β-blocker, but only 23% reached the target dose. This target dose percentage is clearly far from optimal, but it does reflect “real world” management of heart failure. Ivabradine administration on top of β-blocker resulted in (further) heart rate reduction, and apparently in a significant reduction in the primary end point of cardiovascular death or hospital admission. SHIFT thus supports the use of ivabradine to reduce major risks associated with heart failure in patients receiving guidelines-based treatment.

In conclusion, registries, national surveys, and even randomized controlled clinical trials suggest that achieving what has been defined as β-blocker target doses is a utopia in the clinical practice of heart failure management. Targeting heart rate reduction by a dual-drug regimen that respects the patient’s tolerance and (perceived) well-being appears, based on the results of SHIFT, to be the best strategy to achieve better compliance and outcome in terms of mortality and morbidity. _

References
1.Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J. 2008;29: 2388-2442.
MERIT Investigators. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT- HF). Lancet. 1999;353:2001-2007.
3. Packer M, Coats A, Fowler M, et al; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS). N Engl J Med. 2001;344:1651-1658.
4. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomised trial. Lancet. 1999;353:9-13.
5. Flather M, Shibata M, Coats A, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-225.
6. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.




5. H. Krum, Australia


Henry KRUM, MBBS, PhD, FRACP,
FESC, FCSANZ
Professor Director, CCRE in Therapeutics
School of Public Health, Monash University
Department of Medicine, Alfred Hospital
Melbourne, Victoria
AUSTRALIA

(e-mail: henry.krum@monash.edu)


Guideline authorities mandate lifesaving drugs for the treatment of heart failure (HF), to be given at target doses used in definitive outcome trials establishing their benefit.1,2 However, it is clear that in everyday clinical practice, physicians and patients are unwilling or unable to achieve target doses. This has been well established from epidemiological datasets, and also evaluation of background therapy in randomized clinical trials of new therapies.3,4 These observations raise two key questions: (i) can optimal dosing actually be achieved in routine clinical practice?; and (ii) does it really matter whether it can be achieved?

Concerning the first question, in the recent Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT),4 where dose of background β-blocker was critical to interpretation of the results and optimal use strongly encouraged, only 26% of patients were able to reach target dose of β- blocker. Reasons given for not being able to reach target dose reflected the real world, with hypotension and fatigue the predominant explanations. Additionally, 11% of participants did not receive a β-blocker because of chronic obstructive pulmonary disease/asthma, hypotension, or other factors. Nevertheless, 56% of patients reached at least 50% of target dose. This leads to the second question of whether it actually matters. It seems the answer depends on the drug class. For β- blockers, there is only limited evidence from dose-ranging studies focused on surrogate end points like ventricular function. Nevertheless, in Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA), higher doses were more effective on ventricular remodeling, and major events were lower at higher doses (although there were more withdrawals for adverse events). Studies of angiotensin-converting enzyme inhibitors have largely failed to show a true dose response for major cardiovascular outcomes. In Assessment of Treatment with Lisinopril and Survival (ATLAS), despite a large dosing differential between low and high doses of lisinopril, there was only a very small, borderline significant, effect on the combined death and HF hospitalization end point and no significant impact on all-cause mortality. The recent Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study of high- versus low-dose losartan suggested that higher doses may have greater benefit, at least on the primary combined morbidity/mortality end point, if not death alone, but with more adverse events. On this basis, guideline recommendations remain that patients and physicians aim to reach target dose. However, with increasing personalization of therapy, the issue arises as to whether there are better approaches to maximizing drug efficacy than target dose alone. Heart rate (HR) is thought to be an important component of the therapeutic benefit of β-blockers5 (reinforced by the recent SHIFT HR analysis).6 If so, perhaps titration of dosage according to change in HR (or achieved HR) may be a more logical approach to their administration. Similarly, for drugs that manipulate neurohormonal systems, titrating to a target specific to the system manipulated (or a general target like plasma brain natriuretic peptide [BNP]) may be more logical than following generic dosing recommendations. A further consideration is the “cost” of higher doses in terms of increased drug-related adverse events. Finally, the emerging ability to rapidly delineate the individual genomics and proteomics of the patient may assist with greater individualization of drug choice and dosage.

All of that is for the future. For the present, we are left with a situation in which patients cannot reach target doses despite strong guideline recommendations. Clearly education is still required among prescribers to optimize achievable doses of HF drugs. Nevertheless, there would still be a significant percentage of patients who cannot reach target dose. This matters at the population level, but does it matter for the individual? We are at present unfortunately unable to definitively answer that question. _

References
1. Dickstein K, Cohen-Solal A, Filippatos G, et al; Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology; Vahanian A, Camm J, De Caterina R, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
2. Hunt SA, Abraham WT, Chin MH, et al; American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
3. Krum H, Carson P, Farsang C, et al. Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT. Eur J Heart Fail. 2004;6(7):937-945.
4. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
5. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865-869.
6. Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886-894.




6. Lip Ping LOW, Singapore


Lip Ping LOW,MBBS, FRACP,
FAMS, FACC, BBM
Consultant Cardiologist
Low Cardiology Clinic
3 Mt Elizabeth #1105
Mt Elizabeth Medical Centre
228510
SINGAPORE

(e-mail: lowlping@singnet.com.sg)


Chronic heart failure is a major public health problem, and is associated with high morbidity and mortality. A number of large double-blind controlled trials in the last three decades have provided evidence for the efficacy and safety of a number of pharmacological treatments for heart failure. The cornerstone of pharmacological treatment is the use of β-blockers and angiotensin-converting enzyme inhibitors. Based on the drug dosages used in the aforementioned large trials, major guidelines on heart failure—including the updated guidelines from the European Society of Cardiology and the American College of Cardiology/American Heart Association—recommend titration of the doses of these agents to the target dose used in the clinical trials. A number of studies have revealed, however, that a significant number of patients receive doses of these medications that are lower than the target doses. The EuroHeart Failure Survey reported that on average, the daily dosage of β-blocker was far below target doses. In the Impact-Reco II Program, 23% of patients received the target dose, and 54% received 50% or more of the target dose. In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), 56% of patients on β- blockers were treated with at least 50% of the target dose, and 26% reached the target dose.

Common reasons given by physicians for patients not receiving target doses are hypotension, fatigue, and in the case of β-blockers, bronchospasm (especially in smokers). The target doses of medications, particularly β-blockers, defined in morbidity-mortality trials in heart failure patients, may therefore be difficult to achieve in a significant proportion of patients in clinical routine. Moreover in a meta-analysis of β- blocker trials in heart failure, no significant relationship between all-cause mortality and β-blocker dosing was observed, and the benefit on mortality was related to the heart rate reduction achieved in each individual trial.

The recent SHIFT, which showed that heart rate reduction with ivabradine reduced clinical events in heart failure in relation to the heart rate achieved, confirms that heart rate is a risk factor in heart failure, and suggests that guidelines on heart failure may now need to consider heart rate reduction as a target for treatment. _

Further reading
– Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008. Eur J Heart Fail. 2008; 10:933-989.
– Hunt SA; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46: e1-e82. Erra-tum in J Am Coll Cardiol. 2006;47:1503-1505.
– Komajda M, Follath F, Swedberg K, et al. The EuroHeart Failure Survey programme— a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J. 2003;24:464-474.
– de Groote P, Isnard R, Clerson P, et al. Improvement in the management of chronic failure since the publication of the updated guidelines of the European Society of Cardiology. The Impact-Reco Programme. Eur J Heart Fail. 2009;11: 85-91.
– Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
– McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794.




7. V. Mareev, Russia


Viacheslav MAREEV,MD, PhD
M. V. Lomonosov Moscow State University
Moscow, RUSSIA

(e-mail: prof_mareev@ossn.ru)


This is not only a medical question, but a philosophical one. What does “target dose” mean for clinical practitioners? Taking into account themagnitude of the problem and the space for discussion, I will discuss this using the example of β-blocker dosing in chronic heart failure (CHF) patients. Recommendations for optimal doses usually come from randomized clinical trials. But optimal doses often differ in clinical trials, so it is not easy to interpret data.
Officially, target doses of bisoprolol 10 mg/day, metoprolol 200 mg/day, and carvedilol 25 mg twice daily are recommended for CHF patients. These are based on results from Cardiac Insufficiency BIsoprolol Study II (CIBIS II), Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), and Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS). However, practitioners are often afraid of β-blocker side effects and use substantially lower doses due to concerns for patient safety. Race, sex, age, body weight, liver and renal function, disease severity, and metabolism are all important when considering the abstract “target dose.”

Post hoc analysis of MERIT-HF revealed that patients tolerating >100 mg daily or <100 mg daily of metoprolol had the same heart rate (HR) decline and similar improvement in mortality and hospitalization. In CIBIS II, only 42% reached 10 mg bisoprolol, while 33% stayed on doses of 1.25-3.75 mg. As in MERIT-HF, patients on the lowest doses were older with more severe CHF, lower blood pressure, and concomitant complications. Doctors were simply afraid to uptitrate the _-blockers in these patients! Again, significant morbidity and mortality reduction was reached with all doses. In a recent meta-analysis, it was clear that HR decline during treatment should be taken into account for optimal CHF treatment. Of course, modern recommendations are that doctors should uptitrate β-blockers, balancing the usefulness against possible harm. Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) showed that HR reduction with ivabradine, which decreases HR without affecting blood pressure and conduction, plus β-blockers, resulted in morbidity and mortality improvement in CHF patients. Is this a result of ivabradine itself, or just HR decrease? If the latter, is it possible to gain the same result just by uptitrating β-blockers? In terms of evidence-based medicine, this question will be unanswered until a trial compares uptitration of β-blockers with combination of β-blockers and ivabradine. It is important to understand whether CHF patients receiving ivabradine were already on an optimal dose of β-blocker where they failed to reach an optimal HR of below 70 beats per minute. In Morbidity-mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL), nearly 90% of patients with coronary artery disease and left ventricular dysfunction received mean β-blocker doses <50% of the recommended dose. In EuroHeart Failure Survey, we see practically the same mean β-blocker doses in clinical routine in 13 European countries. In SHIFT, 56% of patients received >50% of the maximal dose, and 26% reached the optimal β-blocker dose. This is still well above clinical practice. In a recent Swedish registry, for example, only 10.8% of patients received target doses of β-blockers, and only 20.6% received >50% the maximal dose.

So we can conclude that normally practicing doctors use about half the target dose of β-blocker in CHF treatment, and administration of ivabradine doesn’t change this practice. Although we must try to uptitrate, there is no real possibility of reaching recommended target β-blocker doses in the near future in clinical routine. In a Russian registry, 46% of patients receiving β-blockers didn’t reach the recommended HR of <80 beats per minute. Thus, administration of medications that reduce HR and are not contraindicated with β-blockers could be useful for the successful treatment of CHF. _

Further reading
– Task Force for the diagnosis and treatment of CHF of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: full text (update 2005). Eur Heart J. 2005;26(22):2472.
– MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERITHF). Lancet. 1999;353:2001-2007.
– McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann InternMed. 2009: 150:784-794. – Swedberg K, Komajda M, Bohm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo controlled study. Lancet. 2010;376:875-885.
– Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J. 2009;30:2337-2345.
– Komajda M, Follath E, Swedberg K, et al. The EuroHeart Failure Survey programme— a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J. 2003;24:464-474.




8. K. McDonald, Ireland


Ken McDONALD,MD, FRCPI
Heart Failure Unit
St Vincent’s University Hospital
Dublin, IRELAND

(e-mail: kenneth.mcdonald@ucd.ie)


Over the last two decades, there have been significant advances in the pharmacological management of heart failure. Large international clinical trials have demonstrated the impressive impact of β-blockade and therapies modulating the renin-angiotensin-aldosterone system in improving the outlook for patients with reduced ejection fraction heart failure. Beyond clinical trials, the remaining challenge is to apply these advances in the most effective manner to the general heart failure population. This critical last step in the process poses some questions and challenges.

As a result of the large body of evidence from clinical trials, guidelines have been developed that outline a best-practice approach to the pharmacotherapy of heart failure. The purpose of these guidelines is to improve the overall adherence to what is felt to be “best practice.” They recommend stepwise incremental dose increases of these proven agents, with the aim of achieving clinical trial doses. However, several surveys have demonstrated disappointing application of this guideline approach in clinical practice.

There are two major reasons for the less than impressive uptake of the guideline approach. The differences between clinical trial populations and the community heart failure patients have been well described. The latter tend to be on average a decade older, are more likely to be female, and have a greater number of comorbidities, especially those that may alter drug metabolism. As a result, many experienced practitioners, while accepting the evidence base of guidelines, are of the opinion that they need to be applied cautiously in the community population, and that single-mindedly striving for clinical trial doses may not have the same benefit as observed in trials. Indeed, some feel that dogmatic adherence may in some cases exchange the symptoms of heart failure for those related to the treatment of the condition.

What is missing in present-day pharmacological management of heart failure to help guide how much therapy to apply is an objective indicator of when enough therapy has been applied. Natriuretic peptide is being increasingly used to titrate therapy to more effective levels, and may in the future be used on its own or in combination with other markers to show when sufficient therapy has been applied. Such attempts at individualization of therapy will be important in our efforts to improve application of therapy in an effective manner.

While this may explain some of the failure to apply guidelines, a more fundamental problem is the lack of a formal structure of care for patients with heart failure. It has been well demonstrated that physicians experienced in heart failure management apply proven therapies in a more effective manner. Furthermore, disease management programs led by specialist physicians have applied the necessary structure to encourage effective use of heart failure therapies. However, the majority of patients with heart failure do not receive this structure of care, reducing their likelihood of receiving bestpossible pharmacotherapy.

Therefore, to encourage optimal application of guidelines to the community population, we need to encourage widespread use of disease management programs, and within this structure, assess the relative merit of proven therapies in each individual case. In doing so, it may emerge that in certain situations, striving for clinical trial dosing may be inappropriate, but at least this will be decided within a structure of care that attempts to bring best-possible therapy to the wider heart failure population. _



9. J. Rajadurai, Malaysia


Jeyamalar RAJADURAI,FRCP,
FACC, FESC
Consultant Cardiologist
Sime Darby Medical Center
Kuala Lumpur
MALAYSIA

(e-mail: rjeyacardio@gmail.com)


Globally, the prevalence of heart failure is increasing with aging of the population. Heart failure due to depressed systolic function is an important cause of morbidity and mortality. For many years, treatment consisted only of medications such as digitalis and diuretics. Since the late 1980s however, several landmark clinical trials have revolutionized the management of systolic heart failure with the introduction of neurohormonal blockade, and have clearly established the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists as standards of care. These agents have been shown to significantly reduce all-cause mortality, reduce hospitalizations, and improve quality of life.

All clinical guidelines recommend that patients with systolic heart failure be commenced on these classes of drugs, using the same agents that were tested in the randomized trials, in a similar manner, and at the same doses used. However, in real life, although these medications are initiated in the majority of patients with systolic heart failure, the doses used are often suboptimal and there is a reluctance to uptitrate to target dose.1,2

The reasons for this are multifactorial and are both patient related and doctor related. They include side effects such as symptomatic hypotension, bradycardia, worsening renal function, and hyperkalemia. Individuals—especially the elderly— get confused with the frequently changing dose schedule (from daily to twice daily, and from half a tablet to 1 tablet) and are thus unhappy to have their dose uptitrated. Individuals whose doses are suboptimal (<50% of the target dose) have almost double the mortality of those who take <50% of the recommended dose.1 In fact, the highest-risk patients were found to have the lowest prescription rates for ACE inhibitors, ARBs, and β-blockers.3

The majority of individuals in the community with systolic heart failure do not fulfill the entry criteria for enrollment into the randomized controlled trials. These include the elderly (over the age of 80 years), those with serum creatinine of more than 300 μmol/L, asthmatics, those with chronic obstructive airway disease, those with a history of sustained arrhythmias, those on antiarrhythmic drug therapy, and those having automatic implantable cardioverter defibrillators. Thus there is a lack of evidence-based knowledge on how best to treat these patients, the majority of whom can only tolerate suboptimal doses of ACE inhibitors (or ARBs), β-blockers, and aldosterone antagonists.

The recently published Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) provides some answers. When added on to standard heart failure medications at the doses that reflect practices in real life, ivabradine produced a statistically significant reduction in major cardiovascular events. Ivabradine produced a reduction in heart rate in patients who were unable to tolerate higher doses of β-blockers. It was well tolerated and there was only a single uptitration— from 5 mg twice daily to 7.5 mg twice daily.4

The challenge of the future is to find ways to address the “treatment gap” that exists in a majority of our patients. _

References
1. Lenzen MJ, Boersma E, Scholte OP, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J. 2005;26:2706-2713.
2. Brunner-La Rocca HP, Capraro J, Kiowski W. Compliance by referring physicians with recommendations on heart failure therapy from a tertiary center. J Cardiovasc Pharmacol Ther. 2006;11:85-92.
3. Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA. 2005;294:1240-1247.
4. Swedberg K, Komajda M, Bohm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.




10. K. Sliwa, South Africa


Karen SLIWA,MD, PhD, FESC, FACC
Hatter Institute for Cardiovascular
Research in Africa
Department of Medicine and IIDMM
Faculty of Health Sciences
Cape Town
SOUTH AFRICA

(e-mail: sliwa-hahnlek@mdh-africa.org)


Current guidelines for the management of heart failure recommend uptitrating the doses of drugs to target doses defined in a number of morbidity and mortality trials. Long-term adherence to the recommendations in “real life” is disappointing, and the average dose of the majority of pharmacological treatments remains below the recommended dose. There are a number of factors responsible for this; ie, health systems, patients, physicians, and treatment factors (Table), with different levels of significance in certain patient subpopulations.

One of the most important issues in clinical practice is the lack of communication between physician and patient. Health systems worldwide are under increasing pressure to be time efficient and cost effective, resulting in patients not being allowed to admit that they cannot tolerate their medication and that they are simply not taking it. This denies the patient the opportunity to explore other better-tolerated treatment avenues with their physician. Treating the hypotensive stable patient with poor left ventricular contractility, but tachycardia remains a challenge. We are still miles away from patient-tailored therapy based on genetic profiling, and therefore dogmatic enforcement of guideline-based recommendations is controversial. Apart from mortality, even the end points for successful short-term and long-term outcomes are under debate. Heart rate is one of the most informative and simple parameters that can be measured in cardiovascular disease. However, it is often not taken in a standardized fashion; ie, body posture, duration of measurements, and environmental temperature are not taken into account. _





11. B. D. Westenbrink, W. H. van Gilst, The Netherlands


B. Daan WESTENBRINK,MD, PhD
Department of Cardiology, Thoraxcenter
University Medical Center Groningen
Hanzeplein 1, P. O. Box 30001
9700 RB Groningen
NETHERLANDS

(e-mail: b.d.westenbrink@thorax.umcg.nl)


Pharmacological therapy has dramatically improved heart failure (HF) morbidity and mortality, and remains the cornerstone in disease management. The efficacy of the expanding list of HF drugs has been established in meticulously controlled trials employing careful drug titration protocols aiming for the same target dose in all patients. Clinical practice guidelines therefore recommend titrating all HF patients to the target doses that were used in the original trial protocols. A recent European survey showed that most HF patients received appropriate drugs, yet only 25% were prescribed the recommended target dose.1 This prompts the question of whether 75% of HF patients are undertreated, or whether the target doses are unrealistic.

Aiming for a high target dose with an established safety profile and clear survival benefits appears both sensible and feasible. The superiority of higher over lower doses of several HF drugs has been established in direct comparisons and metaanalyses. In Assessment of Treatment with Lisinopril And Survival (ATLAS), a high lisinopril dose significantly improved outcome compared with a tenfold lower dose.2 Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan (HEAAL) reported similar findings with losartan in patients receiving contemporary background medications.3 Patients in the high-dose group experienced more side effects (mild), but discontinuation of the study medication was sparse and comparable between groups. Furthermore, with intense counseling and careful titration protocols, multidisciplinary HF clinics often manage to increase drug dosage.4 Bridging the gap between guidelines and clinical practice thus appears feasible, suggesting that guideline compliance can be improved.

There are, however, important differences between the general population and trial populations. A mere 13% of European HF patients would have met the inclusion criteria of several landmark trials.5 Patients with preserved ejection fraction, advanced age, significant comorbidities, and women were often excluded.5 While the efficacy of these drugs in the excluded population is not disputed, they do exhibit different pharmacokinetic and pharmacodynamic properties that limit extrapolation of dose recommendations. In Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS), which specifically included elderly patients, the target dose of nebivolol was tolerated in only 68%.6 A closer look at other landmark trials also reveals target doses often not tolerated. In Studies of Left Ventricular Dysfunction (SOLVD) and Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS), for instance, the mean dose of the investigational drug was 56% and 74% of the target dose, respectively.5 Furthermore, in many trials, there were no restrictions on the dosage of background medications, suggesting that targets might have been met at the expense of lower doses of other drugs. If the targets doses cannot be reached in trial participants, why should it be different in real life? Indeed, multidisciplinary HF programs may be successful in increasing dosages, but the actual target dose is seldom reached.4

Dose titration is an essential component of effective pharmacotherapy, allowing us to establish the optimal dose for an individual patient. The large interindividual variations in dose response and toxicity necessitate a tedious titration process that requires commitment from patients and caregivers alike. The relatively low dosing of HF drugs in clinical practice suggests suboptimal dose titration that should be improved. Failure to achieve target doses does not necessarily result from negligence, since the target doses are often not tolerated even in the most controlled settings.

Thus, instead of dogmatically enforcing unrealistic targets and chastising physicians who fail to reach these goals, we should encourage titration of medication to the maximal tolerated dose in all HF patients. More may be better, but a little is better than too much. _

References
1. Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2010;12: 1076-1078.
2. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999;100:2312-2318.
3. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus lowdose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840-1848.
4. Jain A, Mills P, Nunn LM, et al. Success of a multidisciplinary heart failure clinic for initiation and up-titration of key therapeutic agents. Eur J Heart Fail. 2005;7: 405-410.
5. Follath F. Challenging the dogma of high target doses in the treatment of heart failure: is more always better? Arch Cardiovasc Dis. 2009;102:785-789.
6. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-225.